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The Pharmacokinetics and Pharmacodynamics of CNS-acting Agents

The second part of my research project investigated the in vivo relevance of the PEPT2 transporter on systemic exposure, tissue distribution, and renal handling of the endogenous dipeptide carnosine after a 1 nmol/g intravenous dose in wild-type and Pept2 null mice. PEPT2 ablation resulted in a 2-fold increase in systemic clearance of carnosine resulting in a decreased systemic exposure of dipeptide. Carnosine uptake was substantially reduced in the kidney and renal clearance increased 17-fold due to decreased fractional reabsorption of carnosine. This finding reflected the ability of PEPT2 to mediate 83% of carnosine's total reabsorption in tubular fluid. The cerebrospinal fluid to plasma concentration ratios for carnosine were 8-fold greater in Pept2-deficient versus Pept2 -competent mice. The results demonstrate that PEPT2 is the predominant peptide transporter in the physiological handling of carnosine in kidney, and that it significantly limits carnosine exposure in cerebrospinal fluid. These findings suggest that Pept2 may act as a gene modifier for a variety of pathophysiological conditions in the kidney and brain, and that it may serve as a potential target for pharmacological interventions.

... compliance with the Institutional Review Board/Independent Ethics Committee
(IRB/IEC) and International Committee on Harmonization (ICH) Good Clinical
Practice guidelines. Each subject received an oral dose of either lorazepam 2 mg
, ...